Antibiotic overuse may give bacteria an evolutionary boost

Switches bugs into a high mutation state, fueling adaptation.

Multiple drug-resistant Staphylococcus aureus bacteria seen under an electron microscope.

Photo: CDC

By flooding our environment with antibiotics, people may alter a little-appreciated but profound aspect of bacterial evolution: the very pace at which it occurs. Bacteria may evolve more rapidly and more radically than just a few decades ago.

This proposition is still a hypothesis, but it’s an intriguing one. While drug resistance is a well-known consequence of antibiotic use, a global acceleration of bacterial mutability could make drug resistance more common and shape pathogens in unpredictable ways.

"Human activities might be altering the fundamental tempo of bacterial evolution," write geneticists Michael Gillings of Australia’s Macquarie University and Hatch Stokes of the University of Technology in a June Trends in Ecology and Evolution paper.

Gillings and Stokes start by describing what’s widely known: The world is inundated by antibiotics. Drugs consumed by people or contained in consumer products end up in sewage, where they’re unaffected by waste treatment and become part of water cycles. The same goes for drugs consumed by animals, which in the United States accounts for 80 percent of antibiotic use. Antibiotic-rich manure is routinely spread on farms.

'Baseline bacterial evolution is a bell-shaped curve, and we are pushing that curve.'

Subjected to environments that favor drug-tolerating individuals, bacteria have evolved in predictable ways, and antibiotic resistance has reached near-crisis proportions. Historical scourges like tuberculosis and pneumonia have returned with a vengeance. Physicians are running quickly through a shrinking roster of still-effective drugs. Because bacteria easily swap genetic material, genes that neutralize antibiotics aren’t just found in target pathogens, but have diffused throughout the world’s microbial populations.

That much is obvious. But according to Gillings and Stokes, something more subtle could be happening. It stands to mathematical reason that natural selection in antibiotic-flooded environments wouldn’t only favor microbes possessing superbug genes, but microbes with especially high mutation rates that increased their chances of randomly producing a superbug mutation.

"Rates of evolution are themselves selected for higher evolvability," said Gillings. "Baseline bacterial evolution is a bell-shaped curve, and we are pushing that curve to the right."

Mechanisms exist that allow bacteria to become more evolvable. When bugs are exposed to environmental stress, what’s known as an SOS response kicks in, diverting cellular energies to repairing DNA and inducing new mutations.

Bacterial mutations also arise through a mix-and-match recombination of genetic command elements called integrons. A bacterium may contain hundreds of integrons, most of which are inactive at any given time—but in response to stress, dormant integrons become active.

Another source of mutations is lateral gene transfer, in which pieces of genetic material float freely between microbes. Individual genes can be exchanged in this manner, as can entire arsenals of genetic units, such as the NDM-1 resistance factor that emerged in India in 2010 and breaks down entire classes of common antibiotics.

Using these mutation mechanisms comes at a heavy cost to individual microbes, noted Mark Toleman, a Cardiff University microbiologist who studies NDM-1. "The general direction of this change is down hill and detrimental to the genome of the bacteria," he said.

According to Gillings and Stokes, antibiotic ubiquity makes that price worthwhile for many bacteria. "We are flooding the world with selective agents," said Gillings, and this may have changed the standard cost-balance equations that govern whether higher evolvability is worth the costs. It’s better to be alive and damaged than dead.

The researchers say these increased mutation rates will generate new forms of antibiotic resistance and other, as-yet-unpredicted changes. "The processes we describe apply equally to all genes in bacterial genomes, not just those that deal with resistance," Gillings said—and it won’t only be a few disease-causing pathogens that speed up, but many if not most microbes.

Not everyone is convinced. Evolutionary biologist Joanna Masel of the University of Arizona, a specialist in bacterial evolvability, said it’s not yet known whether selection pressures exerted by antibiotics are significantly more intense than other forces shaping bacterial evolution.

"There’s a lot of selection pressure on bacteria all the time. They are fighting off viruses and other parasites. They are evading predators. They are having cutthroat competitions" with other bacteria, Masel said.

"Antibiotics clearly matter. Bacteria have evolved in response to them," Masel continued. "But it’s quite another claim that such evolution is a bigger deal than the many, many other things that make bacteria evolve all the time."

"We could be wrong," Gillings said. "What is needed is for people to think about this problem and to design experiments to test our ideas."

Continued Gillings, "We need key data to be sure, but even if there is only a one percent chance that we are right—and I believe it’s more like 99 percent—it’s a phenomenon that needs to be seriously considered."

40 Reader Comments

perhaps the mutation rate is increasing because the less effective antibiotics are giving bacteria more time to reproduce and hence mutate. the antibiotics already killed off the parts of the population that were originally vulnerable, and left a population with other "naturally" developed resistances besides those forced by the use of antibiotics. the microbes are now resistant to many things and can reproduce (read: genetically recombine) at will and increase the mutation rate.

I think deas187 is right on the money. Antibiotics just don't kill the more resistant bacteria in the system, leaving behind a population that is naturally more resistant, but this is directly a result of our invention of antibiotics. So in this respect, yes bacteria in general is becoming more resistant, but that's only because the weak bacteria is dead, so naturally it appears like its population growth is increasing.

@deas187: Antibiotics haven't created purely resistant microbe populations. It has "merely" increased the percentage of microbes with resistance and allowed new resistances to spread more effectively (in an antibiotic-free environment resistance is generally wasteful, so it tends to occur rarely and spread slowly).

Seeing how the current microbe-response is proving quite effective, I don't really see why they'd need increased mutation rates (except on a localized basis in hospitals etc). But I'm far from an expert, and it definitely sounds like a worthy field to study closer.

I would bet $10 million these guys are right (if I only had $10 million

It's survival of the fittest in such a simplistic an ungodly state. Trillions upon trillions of microbes, the weakest and slowest (reproducing/evolving) die off due to peoples inability to attempt to fend for themselves on the micro-scale (I have a cough, I absolutely must get disease-killing pills (it couldn't possibly be that you need to change your air filters...)) They get these things and the microbes targeted mutate 1000 times within a single persons body before being transmitted to others. The trend continues and all the weak parts have been nearly completely lost from their dna structures. The microbes that survived, mutated, split, mutated again are no longer effected by these drugs. Now we need new drugs, and the process starts over each year (or few months?) Every time we do this, we slide that curve just a little to the right and multiply that by 50whatever+ years of this... I realized this in 3rd grade and stopped taking antibiotics then (about 18 yrs ago). I haven't had flu shots or anything else since then.

I had a 20 min philosophical(?) debate with a biology professor a few years ago about this. My stance was we should stop antibiotics nearly entirely.

Yep. I was given antibiotics for an infected tooth. I never took any drugs before or after (save for over the counter pain killers). The antibiotic completely screwed up my GI bacterial flora. That was 5 years ago, and I still have GI issues and still have to eat a special diet and take probiotics. It sucks. I'm convinced that this will turn ugly when I get older. Bacterial infections are apparently a leading cause of GI cancers.

@deas187: Antibiotics haven't created purely resistant microbe populations. It has "merely" increased the percentage of microbes with resistance and allowed new resistances to spread more effectively (in an antibiotic-free environment resistance is generally wasteful, so it tends to occur rarely and spread slowly).

Seeing how the current microbe-response is proving quite effective, I don't really see why they'd need increased mutation rates (except on a localized basis in hospitals etc). But I'm far from an expert, and it definitely sounds like a worthy field to study closer.

isn't resistance merely a game based on chance mutations and external pressures? a microbe is resistant to some "thing" and that this "thing" happens to be present. the resistance would not be noticed unless there was that external pressure to force it across the population.

as for the mutation rate, maybe it's the detection rate of mutations that we are noticing. if the mutation rate for one microbe is 1% per reproduction, can one say it's 1% for the entire population?

I believe it. Further, I believe that allowing your immune system to actually do it's job rather than taking antibiotics makes it vastly more effective at it's evolved task.

I take no medications that haven't been required by the school system or surgery, other than the occasional alleve for migraines. I've been sick less often in my 32 years of life than most people are in a single year. (Twice, by the way; once in elementary school, once last year.)

isn't resistance merely a game based on chance mutations and external pressures? a microbe is resistant to some "thing" and that this "thing" happens to be present. the resistance would not be noticed unless there was that external pressure to force it across the population.

Kind of. Antibiotic resistance can be acquired by several mechanisms. Tetracycline (a bacterial protein synthesis inhibitor) resistance is a useful example for discussion here. The simplest mechanism of resistance is point mutation within the 30S subunit of the bacterial ribosome, that weakens (or inhibits) tetracycline binding.

A more sophisticated mechanism is afforded by expression of tetracycline/H+ antiporter protein (strictly speaking, one of a family of 22 Tet efflux proteins) in the bacterial cell membrane that actively pumps the drug out of the cell. These proteins are often found on transposons (small, 'mobile' pieces of DNA) that are readily transferred between bacterial species), and so can quickly spread through a population.

Similar phenomena exist for other classes of antibiotics; either the drug is metabolised or modified by the cell (e.g. pencillin/beta-lactamases) or binding of the drug to its cellular target is inhibited (atovaquone/Plasmodium cytochrome b). To return to your original point, often these resistance mechanisms come with an associated fitness penalty to the organism in the absence of selective pressure, and so resistance within a population may be lost over time.

I believe it I hardly ever medicate (unless it is for pain because unlike my immune system my pain tolerence bites) and I haven't required heavy antibiotics since a lymph node back up/infection/lymphoma scare in 7th grade. I dont even get winter colds and haven't had strepp in I don't even know how many years. I wash my hands but refuse to use hand sanitizer and dont whipe everything down with wipes like these new moms do because I value my immune system and thiink it does a great job.

however I will be honest I do get my Influenza shot every fall. I got Influenza freshman year (missed finals, but still went to see RoTK- high school priorities) and it felt like I got hit by a Mack truck and then backed over again. Never again will I experience that again if I can help it.

I believe it I hardly ever medicate (unless it is for pain because unlike my immune system my pain tolerence bites) and I haven't required heavy antibiotics since a lymph node back up/infection/lymphoma scare in 7th grade. I dont even get winter colds and haven't had strepp in I don't even know how many years. I wash my hands but refuse to use hand sanitizer and dont whipe everything down with wipes like these new moms do because I value my immune system and thiink it does a great job.

however I will be honest I do get my Influenza shot every fall. I got Influenza freshman year (missed finals, but still went to see RoTK- high school priorities) and it felt like I got hit by a Mack truck and then backed over again. Never again will I experience that again if I can help it.

Wether you use antibiotics or not is irrelevant in this context. The pathogenic bacteria that would make you sick are in your environment, and individual antibiotic use is hardly a blip on their radar... They will still be in contact with antibiotics and hence be selected for resistance.

And in general, a personal anecdote is neither a useful nor a safe way to conduct epidemiological research. The majority of the worlds population don't get sick from resistant bacteria, but that doesn't really tell us anything about why. Literally millions of people engage in the behavior you consider risky (using hand sanitizer, excessive cleaning, habitual medication), yet are as free of infection as you..By all means keep doing what you do, but don't base your trust of medical science on wether or not it fits your personal preferences.

I believe it. Further, I believe that allowing your immune system to actually do it's job rather than taking antibiotics makes it vastly more effective at it's evolved task.

I take no medications that haven't been required by the school system or surgery, other than the occasional alleve for migraines. I've been sick less often in my 32 years of life than most people are in a single year. (Twice, by the way; once in elementary school, once last year.)

This.

Been pretty much the same for me--only exception being Advil or chianti in my case...

We are pretty much overmedicated--I see it with the extended family. Hopefully we can deal with this before the situation becomes dire...

"Antibiotics clearly matter. Bacteria have evolved in response to them," Masel continued. "But it’s quite another claim that such evolution is a bigger deal than the many, many other things that make bacteria evolve all the time."

Isn't this Joanna person responding to the wrong point or have I misread? The article seems to be saying that 'antibiotics not only make bacteria evolve, but evolve faster, which we may not have previously considered' - I can't see it claiming that evolving faster is a 'bigger deal' than other factors?

It seems reasonable that the more stressful and rapidly changing the environment the greater the advantage to short generations / increased mutation rate - conversely an artificially 'ideal' and stable environment would favor longer generations / slower mutation rate. But then it seems reasonable to me that the sun goes around the earth so what do I know?And I think that bacteria are the leading lifeform on this planet - as the argumentative Joanna observes "There’s a lot of selection pressure on bacteria all the time. They are fighting off viruses and other parasites. They are evading predators. They are having cutthroat competitions" - and they've been doing this stuff for about 4 _billion_ years since this planet was a cooling lump of molten irradiated rock that they've terraformed into the current paradise. That we're paving over and building parking lots on... and we think we're smart doh!

This hits on one basic aspect of evolution that gets far to little mention; living things have evolved to evolve. Evolution isn't just the result of selection of accidental variation as it sometimes seems to be portrayed. Instead living things have aggressively adapted to harness selection because the ability to evolve is itself a very power survival trait.

How would use of antimutagenic compounds play into the balance? Most so called 'antibiotics' used for livestock are antimutagenic.

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I realized this in 3rd grade and stopped taking antibiotics then (about 18 yrs ago). I haven't had flu shots or anything else since then.

How did you get from antibiotics to vaccines? Maybe you should adjust your idiocity percentage up a few points.

Vaccines and antibiotics are the same to me. Ever noticed how in September, thousands of people go to hospitals and Walgreens/CVS or other places to get vaccines for the flu. Spread this out over the next few months as shots become available. Then in December a news report shows up saying the current viruses have mutated and a new set of flu shots will be released as available...

All those people just got treated against last years virus; the slight mutations that are cycling the globe are now in the same boat as bacteria. The less power virus mutations just got wiped off the face of the earth (for about 15 years) and the more powerful mutations continue to change making the first round flu shots near worthless. Vaccines consist of a near dead(virus can die?) weakened state virus of previous time periods. Our bodies fight this virus (not to hard) hardening us against the future of: that vaccines origin virus... Mutations over time means we are no longer fighting the origin virus, we are fighting a new virus.

That wouldn't be a problem if viruses didn't act like bacteria and mix-and-match with others causing new versions to be fundamentally different enough that they aren't affected by the baseline vaccine.

This article makes me think of herd immunity, but the other way around: when the general population is pumped with antibiotics for every common cold, the resistant bacteria that develop won't threaten just these people's health, but that of every person that comes in contact with the bacteria. Multi-resistant hospital infections, anyone?

In my case, I'm very wary of taking any kind of medication. I do get migraines and heartburns relatively often and in the worst cases will pop a pill (pain killer or simple antacid). But I will never ever take an antibiotic without a serious reason to do so, i.e. an actual infection.

Still, I wonder how effective this is when I read about people taking antibiotics for no reason, and what's worse, antibiotics being pumped into animals that are turned into meat. Incidentally, this is one reason why I'd become a vegetarian, even though I do love me a bit of rare steak.

I'm reminded of the last time I had strep throat. I had to shell out beaucoup bucks to have an RN shove a popsicle stick down my throat and write a prescription. I knew what I had, what antibiotics are effective for me, and still had to go through an inspection process.

I find it hilarious that a single person has to jump through hoops to get antibiotics, but farmers can practically bathe their livestock in it and no one bats an eyelash.

I know there are differences between bacteria and viruses. I know there is a difference between antibiotics and vaccines. I also realize I am the only one in my family who refuses to take either of those and I am also the only one who catches a light flu every 5 or 6 years. The rest of my family gets shots yearly, takes antibiotics if they get sick and they all get the flu every year, they all catch colds a couple times a year.

I know there are differences between bacteria and viruses. I know there is a difference between antibiotics and vaccines. I also realize I am the only one in my family who refuses to take either of those and I am also the only one who catches a light flu every 5 or 6 years. The rest of my family gets shots yearly, takes antibiotics if they get sick and they all get the flu every year, they all catch colds a couple times a year.

Not commenting on the rest (antibiotics are quite different from vaccines), but taking antibiotics for a flu or cold is dumb. No personal offense to you, but the physicians that are prescribing these things are dumb. They KNOW that antibiotics aren't going to touch a cold, aren't going to touch a flu, but they allow soccer moms who MUST give Johnny something browbeat them into prescribing antibiotics when they don't need it. Instead, the antibiotics kill the benign bacteria and leave the patient more susceptible to harmful bacteria. Mrs Soccer Mom just made it MORE likely for Johnny to get sick, on top of the whole worry about bacterial resistance, gut bacteria, etc.

We need to have a week long instructional course on TV or something to get people to realize that bacteria and viruses are different. Just because it says antibacterial on your favorite lotion doesn't mean you won't get sick. You still need to wash your hands to eliminate the viruses (and dirt/oil/chemicals).

I know there are differences between bacteria and viruses. I know there is a difference between antibiotics and vaccines. I also realize I am the only one in my family who refuses to take either of those and I am also the only one who catches a light flu every 5 or 6 years. The rest of my family gets shots yearly, takes antibiotics if they get sick and they all get the flu every year, they all catch colds a couple times a year.

I'm required to get the flu shot every year and i take my meds when i get prescribed them, but i only get sick about once every several years. My wife is constantly on antibiotics and steroids, but that is because she is a headstart school teacher. With 30 plus kids every day, at least 1/3 of them are either sick, getting sick or recovering from being sick.

What does that mean? Nothing. Everyone has different exposure levels to diseases; just because my wife is constantly taking meds does not mean they are making her sick, it's parents who don't want to deal with a sick kid at home that are making her sick.

I know there are differences between bacteria and viruses. I know there is a difference between antibiotics and vaccines. I also realize I am the only one in my family who refuses to take either of those and I am also the only one who catches a light flu every 5 or 6 years. The rest of my family gets shots yearly, takes antibiotics if they get sick and they all get the flu every year, they all catch colds a couple times a year.

Clearly antibiotics are ineffective against the common cold and the flu. I'd hope that your doctor is prescribing placebos in this instance.

I also hope though for your sake you take antibiotics if advised by a medical professional; septicaemia and bacterial pneumonia aren't much fun. The flu vaccine is of rather limited efficacy (the virus mutates rapidly), however the same is absolutely not true for MMR; I trust you and your family are covered here.

This (mutation rate increases when the environment is stressed) is not a new hypothesis --- it was floated by some Russian biologists in the 1960s, though there were limits to the extent they could test it because of Lysenkoism. Credit where credit is due and all that.

I know there are differences between bacteria and viruses. I know there is a difference between antibiotics and vaccines. I also realize I am the only one in my family who refuses to take either of those and I am also the only one who catches a light flu every 5 or 6 years. The rest of my family gets shots yearly, takes antibiotics if they get sick and they all get the flu every year, they all catch colds a couple times a year.

Not commenting on the rest (antibiotics are quite different from vaccines), but taking antibiotics for a flu or cold is dumb. No personal offense to you, but the physicians that are prescribing these things are dumb. They KNOW that antibiotics aren't going to touch a cold, aren't going to touch a flu, but they allow soccer moms who MUST give Johnny something browbeat them into prescribing antibiotics when they don't need it. Instead, the antibiotics kill the benign bacteria and leave the patient more susceptible to harmful bacteria. Mrs Soccer Mom just made it MORE likely for Johnny to get sick, on top of the whole worry about bacterial resistance, gut bacteria, etc.

In these cases doctors in Sweden (or maybe Norway, one of those cold places over there) write prescriptions for antibiotics that don't become effective until 3 days after they're written. By the time it's valid the virus-caused illness is on the decline and often the scrip goes unfilled. But the important thing is it satisfies the Soccer Mom's psychological need to leave the doctor's office with *something* to validate her snowflake's sickness. Pretty good idea IMO.

In these cases doctors in Sweden (or maybe Norway, one of those cold places over there) write prescriptions for antibiotics that don't become effective until 3 days after they're written. By the time it's valid the virus-caused illness is on the decline and often the scrip goes unfilled. But the important thing is it satisfies the Soccer Mom's psychological need to leave the doctor's office with *something* to validate her snowflake's sickness. Pretty good idea IMO.

Actually, I think it's a terrible idea, if true. Why would any doctor prescribe a drug that's ineffective against the illness they're prescribing for? If antibiotics are prescription-only drugs, as they should be, doctors should send soccer-moms home with something else, or nothing at all.

In these cases doctors in Sweden (or maybe Norway, one of those cold places over there) write prescriptions for antibiotics that don't become effective until 3 days after they're written. By the time it's valid the virus-caused illness is on the decline and often the scrip goes unfilled. But the important thing is it satisfies the Soccer Mom's psychological need to leave the doctor's office with *something* to validate her snowflake's sickness. Pretty good idea IMO.

Actually, I think it's a terrible idea, if true. Why would any doctor prescribe a drug that's ineffective against the illness they're prescribing for? If antibiotics are prescription-only drugs, as they should be, doctors should send soccer-moms home with something else, or nothing at all.

All sound in theory but in reality that's exactly what's happening anyway. And as long as soccer moms can doctor shop until they find what they want, there will be doctors out there who will write it just to shut them up.

Interesting article. I've worked at a microbiology lab at a major metropolitan hospital in the past, and it's definitely true that multi-drug resistance is on the rise across the board. There are a couple of things going on, at least as far as I can see it.

- Doctors talk a lot about how cutting down on antibiotic use is a good thing, but hospitals are places where your sickest people will congregate. These are people who already have decreased physiologic reserve and decreased resistance to infection -- and so you find yourself pulling out "big guns" again and again. On a daily basis in any major clinical microbiology lab in the world, cultures grow out strains of bacteria like Acinetobacter baumanii that are simply resistant to just about everything. Interestingly, at least in the lab in which I worked, these cultures routinely came from samples sent from nursing homes.- The soccer mom phenomenon is real, and unfortunate.- Those who speak of the way we feed antibiotics to our livestock are spot-on. Fluoroquinolone-resistant Salmonella spp. simply weren't seen until the EU and the USA allowed ciprofloxacin to be used on chickens. Not a decade afterward, a good percentage of Salmonella isolates cultured from eggs are resistant. Fortunately, both the EU and the USA have since banned fluoroquinolone use in poultry, but if you ask me the damage is already done.

Many years ago (1970s) my grandfather, who was a doctor/surgeon, encouraged the sparse use of anti-bacterial soaps and other agents because he believed we were "sissifying" ourselves. What doesn't kill you makes you stronger...this quote has far reaching truths!

Many years ago (1970s) my grandfather, who was a doctor/surgeon, encouraged the sparse use of anti-bacterial soaps and other agents because he believed we were "sissifying" ourselves. What doesn't kill you makes you stronger...this quote has far reaching truths!

Right, but that basically means: have a lot of children and see most of them die before reaching puberty.

Many years ago (1970s) my grandfather, who was a doctor/surgeon, encouraged the sparse use of anti-bacterial soaps and other agents because he believed we were "sissifying" ourselves. What doesn't kill you makes you stronger...this quote has far reaching truths!

Right, but that basically means: have a lot of children and see most of them die before reaching puberty.